Naturally occurring non-nutritive agents such as flavonoids, phenolic compounds, glucosinulates, terpenes and many others present in plants are believed to have disease preventive properties. Diets containing some of these substances have been shown to be protective against diseases such as colon and breast cancer in animals (Kuo, S. M. 1997. Clin. Rev. Oncogenesis 8:47-69; Verhoeven et al. 1996. Cancer Epid. Biomark. Prev. 5:733-748; Bradlow et al. 1991. Carcinogenesis 12:1571-1574; Lamartiniere et al. 1995. Proc. Soc. Exp. Biol. Med. 208:120-123). The clinical relevance of such natural phytochemicals is dependent on extrapolation from epidemiological data and from experiments in animal models of diseases of interest.
Resveratrol (3,5,4xe2x80x2-trihydroxystilbene) and its glucoside, cis- and trans-forms occur naturally in foods such as grapes, mulberries, peanuts, and wine. Resveratrol and its related compounds also are found in other plants including a traditional Chinese medicinal plant, the dried roots of Polygonum cuspidatum. These polyphenolic compounds possess many biological activities including antioxidant activity, antimutagenic activity, antiinflammatory activity, anti-tumor promoting activity, as well as demonstrating a preventive effect for cancer (Jang et al. 1997. Science 275:218-220). Resveratrol has also been shown to affect a variety of specific cellular mediators. For example, studies have shown that resveratrol induces nitric oxide synthase (Hsieh et al. 1999. Cancer Res. 59:2596-2601), that resveratrol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced cyclooxygenase-2 gene expression (Subbaramiah wt al. 1998. J. Biol. Chem. 273:21875-21882), that resveratrol inhibits expression of tissue factor and cytokines in vascular cells (Pendurthi et al. 1999. Arterioscler. Thromb. Vasc. Biol. 19:419-426), and that resveratrol inhibits ribonucleotide reductase and DNA synthesis in mammalian cells (Fontecave et al. 1998. FEBS Lett. 421:277-279).
Much attention has been focused on the fact that large amounts of resveratrol are present in red wine and that moderate red wine consumption may reduce the risk of cardiovascular disease (Goldberg et al. 1995. Clin. Chim. Acta 237:155-187). In addition, evidence has accumulated to support a role for resveratrol in prevention of cancer and heart disease (Constant, J. 1997. Coron. Artery Dis. 8:645-649; Fontecave et al. 1998. FEBS Lett. 421:277-279).
WO 9904747 describes the use of resveratrol to improve the appearance of human skin and to enhance differentiation and inhibit proliferation of keratinocytes. Resveratrol in pure form is given as a topical formulation in doses of 0.00002 to 10% resveratrol by weight.
WO 9903816 discloses compositions of resveratrol esters and their oligomers for use as anti-tumor and vasoprotective agents in animals and humans. The resveratrol derivatives are monomer or oliogomers having at least one ester group with the formula xe2x80x94Oxe2x80x94COxe2x80x94A. None of the compounds are resveratrol analogs with hydroxyl or methoxy substitutions on the rings.
WO 9901148 describes compositions containing resveratrol and other polyphenols for the treatment of metabolic disorders such as anoxia. The polyphenols are extracts from grapes and grape products or wine with yeast extracts combined.
A Japanese patent (JP 9328410) discusses the use of an extract of the Yucca plant which contains saponin, flavone and resveratrol as a cosmetic for prevention of rough skin and cutaneous aging. The extract was shown to have antimicrobial activity as well as UV absorbing ability.
CN 1127070 describes use of resveratrol in combination with a variety of other compounds as additives for a nutritional milk powder. The powder was developed for use in the elderly for immunostimulation and prevention of heart disease, as well as a milk powder for pregnant women and children and a health drink for athletes.
U.S. Pat. No. 5,747,536 discloses use of a trihydroxy or tetrahydroxystilbene, such as resveratrol, in combination with L-carnitine and alkanoyl L-carnitine to prevent or treat cardiovascular diseases, peripheral cardiopathies, and diabetic peripheral neuropathies.
Another Japanese patent (JP 61171427) describes use of an extract of Polygonaceae as an anti-thrombosis agent. The extract contains a stilbene compound comprising resveratrol as well as other components.
It has now been found that analogs of the natural product resveratrol with additional hydroxy or methoxy substitutions have biological activity that can lead to disease prevention.
An object of the present invention is composition comprising an analog of resveratrol, preferably a hydroxylated or methoxylated resveratrol including 3,5-dihydroxystilbene (R-1), 3,3xe2x80x2,4,5xe2x80x2-tetrahydroxystilbene (R-2), 3,4,4xe2x80x2,5-tetrahydroxystilbene (R-3), 3,3xe2x80x2,5,5xe2x80x2-tetrahydroxystilbene (R-4), 3,3xe2x80x2,4,5,5xe2x80x2-pentahydroxystilbene (R-5), 3,5-dimethoxystilbene (MR-1), 3,4xe2x80x2,5-trimethoxystilbene (MR-0), 3,3xe2x80x2,4,5xe2x80x2-tetramethoxystilbene (MR-2), 3,4,4xe2x80x2,5-tetramethoxystilbene (MR-3), 3,3xe2x80x2,5xe2x80x25xe2x80x2-tetramethoxystilbene (MR-4), and 3,3xe2x80x2,4,5,5xe2x80x2-pentamethoxystilbene (MR-5).
Another object of the present invention is a method for inhibiting cell growth comprising administering the composition.
Yet another object of the present invention is a method for preventing or treating cancer in an animal which comprises administration of the composition.